KR100546495B1 - Benzonitrile Synthesis Method - Google Patents

Abstract

The nucleophilic substitution reaction in halobenzene is carried out in the presence of a catalyst. More specifically, the present invention provides a process for preparing optionally substituted hydroxybenzoic and alkoxybenzoic acids and optionally substituted hydroxybenzonitrile and alkoxybenzonitriles from substituted 2,6-dihalobenzenes. .

Description

Benzonitrile Synthesis Method

The present invention relates to a process for producing aromatic carboxylic acids and nitriles having alkoxy or hydroxy substituents on aromatic rings.

In particular, benzoic acid or benzonitrile having alkoxy or hydroxy substituents on aromatic rings are used in various commercial fields, including the manufacture of pesticides and pharmaceuticals. Converting amino substituted benzoic acids or esters to alkoxy or hydroxy substituted benzoic acids or esters using various routes, for example, diazo reactions as described in US Pat. No. 5,530,028, or AU-A-12496 / Although it is known to convert 6-chloro-2-methoxytoluene to 3-methoxy-2-methylbenzoic acid using Grignard reaction conditions as described in 83, more Providing low cost and high purity is constantly needed.

It is an object of the present invention to provide some advantageous methods for producing the desired benzoic acid and benzonitrile.

The present invention

(i) reacting a compound of formula (I) with an alkali alkoxide, alkali alkoxide, alkali arylalkoxide or alkali heteroarylalkoxide in the presence of a catalyst comprising optionally copper to produce a compound of formula (IIa); and

(ii) reacting a compound of formula (IIa) with an alkali metal cyanide, acetone cyanohydrin or cuprous cyanide, to a catalyst presence comprising nickel to form an aromatic cyano compound of formula (III) Provided are methods of preparing the compounds of III.

In the above formula,

Each X is independently chlorine, bromine, or iodine,

R is a hydrogen atom, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₂ ) alkyl, heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ the chihoen alkoxy with 1 to 3 substituents independently selected from (C ₁ -C ₆₎ alkyl, aryl, aryl (C ₁ -C ₂₎ alkyl, , Heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl,

R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C ₁ -C ₂₎ alkyl or heteroaryl (C ₁ -C ₂ Alkyl,

R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₅₎ alkyl or (C ₁ -C ₂₎ alkoxy (C ₁ -C ₃₎ alkyl substituted with.

In addition, the present invention

(i) reacting a compound of formula (I) with an alkali metal cyanide, acetone cyanohydrin or cuprous cyanide in the presence of a catalyst comprising nickel to form an aromatic cyano compound of formula (IIb); and

(Ii) reacting a compound of Formula IIb with an alkali alkoxide, alkali alkoxide, alkali arylalkoxide or alkali heteroarylalkoxide in the presence of a catalyst comprising optionally copper to produce a compound of Formula III Provided are methods of preparing the compounds of III.

;

;

In the above formula,

Each X is independently chlorine, bromine or iodine,

R is a hydrogen atom, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₂ ) alkyl, heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ alkoxy substituted with one to three substituents independently selected from (C ₁ -C ₆₎ alkyl, aryl, aryl (C ₁ -C ₂₎ alkyl, Heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl,

R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C ₁ -C ₂₎ alkyl or heteroaryl (C ₁ -C ₂ Alkyl,

R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₅₎ alkyl or (C ₁ -C ₂₎ alkoxy (C ₁ -C ₃₎ alkyl substituted with.

The present invention also provides a process for preparing a compound of formula IVa by hydrolysis of a compound of formula III using a strong acid or strong base, and, if necessary, further adding the compound of formula IV using an ether separation reagent. To convert to.

,

,

In the above formula,

R is a hydrogen atom, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₂ ) alkyl, heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ the chihoen alkoxy with 1 to 3 substituents independently selected from (C ₁ -C ₆₎ alkyl, aryl, aryl (C ₁ -C ₂₎ alkyl, , Heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl,

R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ alkoxy substituted with one to three substituents independently selected from aryl, aryl (C ₁ -C ₂₎ alkyl or heteroaryl (C ₁ -C ₂ Alkyl,

R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₅₎ alkyl or (C ₁ -C ₂₎ alkoxy (C ₁ -C ₃₎ alkyl substituted with.

The present invention further provides a method for preparing a compound of formula IVb by reacting a compound of formula III with an ether separation reagent in a first step, and, if necessary, converting the compound of formula IVb to a strong acid or strong base. To hydrolyze into compounds of formula V.

In the above formula,

R is a hydrogen atom, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₂ ) alkyl, heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ the chihoen alkoxy with 1 to 3 substituents independently selected from (C ₁ -C ₆₎ alkyl, aryl, aryl (C ₁ -C ₂₎ alkyl, , Heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl,

R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C ₁ -C ₂₎ alkyl or heteroaryl (C ₁ -C ₂ Alkyl,

R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₅₎ alkyl or (C ₁ -C ₂₎ alkoxy (C ₁ -C ₃₎ alkyl substituted with.

In such alternative embodiments of the invention, the preferred method is

Each X is independently chlorine or bromine,

R is a hydrogen atom or (C ₁ -C ₆ ) alkyl,

R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl,

The R ² and R ³ each independently represent a case of substituted with a hydrogen atom or a (C ₁ -C ₂₎ alkyl or methoxy (C ₁ -C ₂₎ alkyl.

A more preferred method is that each X is chlorine, R is a hydrogen atom or (C ₁ -C ₃ ) alkyl, R ¹ is CHR ² R ³ and R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₂ ) alkyl phosphorus

If it is.

Even more preferred method is when R is methyl or ethyl, R ² is a hydrogen atom, and R ³ is a hydrogen atom or methyl.

As used herein, the term "alkyl" refers to a straight and branched aliphatic hydrocarbon chain, for example methyl, ethyl, n -propyl, isopropyl, n -butyl, secondary-butyl, tertiary- Butyl, isoamyl and n -hexyl and the like.

The term "alkoxy" means a straight and branched aliphatic hydrocarbon chain attached to an oxygen atom, for example methoxy, ethoxy, n -propoxy, isopropoxy, and the like.

The term "aryl" means an aromatic ring system, for example phenyl, 1-naphthyl, 2-naphthyl and the like,

The term "arylalkyl" refers to an aryl group attached to an alkylene group, for example benzyl, phenethyl and the like.

The term "heteroaryl" refers to an aromatic heterocyclic group. Heteroaryl residues and heteroaryl rings of other groups, such as heteroarylalkyl, typically contain one or more oxygen, nitrogen, or sulfur atoms that can be fused to one or more other aromatic, heteroaromatic, or heterocyclic rings, such as benzene rings. 5 or 6 membered aromatic ring. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, triazinyl, benzofuranyl, benzothienyl, indolyl, quinazolinyl, acridinyl, purinyl and quinosalinyl and the like.

The term "heteroarylalkyl" refers to a heteroaryl group to which an alkylene group is attached, for example perfuryl, tenyl, nicotinyl and the like.

The term "alkali" means a lithium, potassium or sodium atom.

The monoalkoxylation or monoaroxylation reaction used to convert a compound of formula (I) to a compound of formula (IIa) or to convert a compound of formula (IIb) to a compound of formula (III) can be carried out with or without a catalyst. When a catalyst is used, suitable catalysts include copper chloride (I), copper bromide (I), copper iodide (I), copper cyanide (I), copper chloride (II), copper oxide (II), copper sulfate (II) And elemental copper. Copper cyanide (I) is the preferred catalyst. The catalyst comprising copper may exist in various forms, such as powder or copper attached to a carrier, with the powder in particular being particularly preferred. When catalysts are used, the proportions used are based on compounds of formula (I) or formula (IIb). 0.1 to 100 mol%. Preferred proportions are 0.5 to 25 mol%. A more preferable use ratio is 1-10 mol%.

Suitable carriers that can be used to support the copper catalysts include, but are not limited to, silica, carbon, alumina, calcium carbonate, and the like.

Suitable alkali alkoxide reagents used to convert a compound of Formula I to a compound of Formula IIa or to convert a compound of Formula IIb to a compound of Formula III include, but are not limited to, sodium methoxide, potassium methoxide, sodium ethoxy The side etc. are mentioned, for example. Likewise suitable alkali alkoxides include sodium phenoxide, potassium phenoxide and lithium phenoxide and the like. Suitable alkali arylalkoxides include sodium benzoside and the like. Suitable alkali heteroarylalkoxides include potassium tenoxide and the like. Alkali alkoxides, alkali alkoxides, alkali aryl alkoxides and heteroaryl alkoxides are usually used in amounts of 100 to 200 mol%, based on the aromatic compounds substituted with halogens.

In the process of the invention, a single halogen group of the aromatic ring of the compound of formula I can optionally be replaced with an alkoxy, aryl, arylalkoxy, or heteroarylalkoxy group. As an example, in the present invention, 1-alkyl-2,6-dihalobenzene is 1-alkyl-6- (alkoxy or aryl or arylalkoxy or heteroarylalkoxy) -2-halobenzene, with a selectivity of at least 80%. , Monoalkoxylation, monoaroxylation, monoarylalkoxylation or monoheteroarylalkoxylation can be carried out. If preferred conditions are used, the selectivity is 85% or more. Under more preferable conditions, the selectivity is 90% or more. As is known to those skilled in the art, the selectivity is typically higher when the conversion rate is lower. For example, when 2,6-dichlorotoluene reacts with methoxide, the selectivity to 6-chloro-2-methoxytoluene is at least 99% at 70% conversion. If the conversion rate increases to 93%, the selectivity decreases by about 95%.

The reaction rate for substituting a single halogen group is increased when using a suitable solvent or mixture of solvents. Dimethyl Sulfoxide (DMSO), Dimethylformamide

(DMF), 1-methyl-2-pyrrolidinone (NMP), dimethylsulfate, ethyl acetate, and suitable alcohols such as methanol and ethanol are preferred solvents, and DMSO and NMF are more preferred. Reaction is normally performed at 65-160 degreeC, and 90 degreeC or more is preferable.

The cyanation reaction used to convert the compound of formula (I) to the compound of formula (IIb) or the compound of formula (IIa) to the compound of formula (III) is typically carried out in the presence of a catalyst comprising nickel. Such catalysts include, but are not limited to, nickel (II) bromide, mixtures of zinc and triphenylphosphine, dibromobis (triphenylphosphine) nickel, mixtures of zinc and triphenylphosphine, dichlorobis ( Triphenylphosphine) nickel, mixtures of zinc and triphenylphosphine and tris (triphenylphosphine) nickel and the like. Such commercially available catalysts may be used in combination. The catalyst is usually used in an amount of 1 to 10 mol% based on the amount of the aromatic compound substituted by halogen.

Suitable cyanide reagents include, but are not limited to, sodium cyanide, potassium cyanide, lithium cyanide, cyanohydrins such as acetone cyanohydrin, copper cyanide, and the like. Typically cyanation reagents are used in amounts of 100 to 200% molar equivalents based on the aromatic compounds substituted by halogen.

Suitable solvents are often used in cyanation reactions. Alcohols such as methanol and ethanol, tetrahydrofuran (THF), hexamethylphosphoramide (HMPA), acetonitrile (ACN), 1-methyl-2-pyrrolidinone (NMP), toluene and other aromatic solvents can be used. have. Mixtures of suitable solvents may also be used. Preferred solvents are THF, NMP and ACN. The cyanation reaction is carried out at 20 to 200 ° C, preferably at 30 to 180 ° C, more preferably at 40 to 140 ° C. The yield of cyanation reaction is generally at least 50%. When preferred conditions are used, yields of at least 75% are obtained. Using more preferred conditions, a yield of at least 90% is obtained, based on the weight of the starting material.

Conditions known to those skilled in the art can be used to hydrolyze the aromatic cyano compound of Formula III to an acid of Formula IVa or to hydrolyze the aromatic cyano compound of Formula IVb to an acid of Formula V. . The reaction is usually carried out in the presence of a strong acid or strong base. Suitable acids include strong inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, with sulfuric acid being preferred. Suitable bases include sodium hydroxide, potassium hydroxide. The hydrolysis reaction can be carried out at ambient temperature to a temperature of 180 ° C.

Ether separation reactions can be carried out using reactions known to those skilled in the art. For example, this reaction may be carried out by a compound of formula III, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, or the like, a Lewis acid such as boron trifluoride etherate, a base such as sodium methoxide, pyridine or methylamine. Or strong acid-weak base salts such as pyridine hydrochloride, etc.

Heating forms a compound of formula IVb substituted with hydroxy. Suitable reaction temperatures are from ambient temperature up to 200 ° C. In a similar manner, compounds of formula IVa can be converted to formula V.

The following examples and experimental methods are provided as a guide to the practitioner and are not intended to limit the scope of the invention as defined by the claims.

Example 1 Methoxylation of 2,6-Dichlorotoluene (DCT) to 6-chloro-2-methoxytoluene (MCT)

In a 500 mL flask equipped with a temperature controller, a condenser, and a magnetic stirrer, 50 g of DCT (0.31 mol), 30 g of 95% potassium methoxide (0.41 mol) and 25 g of 1-methyl-2-pyrrolidinone (NMP) were charged. The mixture was stirred at 100 ° C. for 2 hours and then at 120 ° C. for 18 hours. Then dimethyl sulfate (10 g, 0.08 mol) was added and the resulting mixture was further stirred at 120 ° C. for 5 hours. After this time, the mixture was cooled to ambient temperature and filtered. The filter cake was washed with isopropanol (3 x 65 mL). Analysis of the mixed filtrate and wash solution showed that 40 g of MCT were produced. Yield 82%.

Example 2 Methoxylation of DCT with CuCN in DMF

To a 25 mL flask equipped with a thermostat, condenser and magnetic stirrer was charged 2.00 g DCT (12.4 mmol), 1.30 g NaOCH ₃ (24.1 mol), 0.10 g CuCN (1.2 mmol) and 10.0 g DMF. The mixture was heated to 120 ° C. and stirred under nitrogen. Gas Chromatography (GC) analysis showed that the yield of MCT was 88.6% after 17 hours, leaving 10.0% of DCT. After 19 hours, the yield of MCTs increased to 92.8%, at which point 1.4% of DCT had not yet responded.

Example 3 Methoxylation of DCT with CuCN in DMF

In a 25 mL flask equipped with a thermostat, condenser and magnetic stirrer was charged 5.00 g of DCT (31.0 mmol), 2.00 g of NaOCH ₃ (37.0 mmol), 0.15 g of CuCN (1.7 mmol) and 5.00 g of DMF. The mixture was heated to 150 ° C. and stirred under nitrogen. Gas chromatography (GC) analysis showed that after 17 hours the yield of MCT was 64.8% and 28.1% of DCT remained. After 26 hours, the yield of MCT increased to 76.0%, at which time 16.3% of DCT had not yet responded.

Example 4 Methoxylation of DCT with CuCN in DMSO

In a 25 mL flask equipped with a thermostat, condenser and magnetic stirrer was charged 5.00 g DCT (31.0 mmol), 2.00 g NaOCH ₃ (37.0 mmol), 0.15 g CuCN (1.7 mmol) and 5.0 g DMSO. The mixture was heated to 140 ° C. and stirred under nitrogen. Gas chromatography (GC) analysis showed that after 6 hours the yield of MCT was 82.8% and 12.4% of DCT remained. After 12 hours, the yield of MCTs increased to 86.1% at which time 7.2% of DCT had not yet responded.

Example 5 Methoxylation of DCT with CuBr in Methanol

A 25 mL flask equipped with a thermometer, condenser and magnetic stirrer was charged with 2.00 g of DCT (12.4 mmol), 5.00 g of 25% NaOCH ₃ solution (methanol solvent, 23.1 mmol), 0.25 g of CuBr (1.7 mmol) and 0.44 g of ethyl acetate. . The mixture was heated to reflux and stirred under nitrogen. Gas chromatography (GC) analysis showed that after 5 hours the yield of MCT was 7.3% and 92.1% of DCT remained. After 24 hours, the yield of MCTs increased to 25.2%, at which time 65.2% of DCT had not yet responded.

Example 6 Cyanation Reaction to Convert MCT to 2-Cyano-6-methoxytoluene

50 mL three-necked flask equipped with reflux condenser, magnetic stirrer and thermostat in nickel (II) bromide (0.22 g, 1.0 mmol), zinc powder (0.20 g, 3.0 mmol), triphenylphosphine (1.31 g, 5.0 mmol ) And 15 mL of tetrahydrofuran were added. The mixture was heated to 50 ° C. and stirred for 30 minutes under nitrogen. After this step, 6-chloro-2-methoxytoluene (4.70 g, 30.0 mmol) was added and then the temperature was raised to 60 ° C. Then, the mixture was further stirred for 30 minutes. Potassium cyanide (2.65 g, 40.7 mmol) was then added gradually over a period of 5 hours or more, divided into 10 portions. At the end of the addition, the mixture was stirred at 60 ° C. for 18 hours. As a result of gas chromatography (GC) analysis, the composition of the reaction mixture at the end of this period was 71.5% 2-cyano-6-methoxytoluene, 22.8% 6-chloro-2-methoxytoluene, 2-methoxytoluene 4.1% and 2,2'-dimethyl-3,3'-dimethoxybiphenyl was found to be 0.5%. The yield of cyanation reaction was 92.6% based on the starting material consumed.

Example 7 Cyanation of 6-chloro-2-methoxytoluene (MCT) to 2-cyano-6-methoxytoluene (CMT)

Process 1 (CCW09-18):

Dibromobis (triphenylphosphine) nickel (1.00 g, 1.34 mmol), zinc powder (0.25 g, 3.82 mmol), triphenylphosphine (50 mL 3-necked flask equipped with reflux condenser, magnetic stirrer and temperature controller) 1.50 g, 5.72 mmol), 6-chloro-2-methoxytoluene (MCT, 10.0 g, 63.8 g), 15.0 g 1-methyl-2-pyrrolidinone (NMP) and 7.5 g acetonitrile were added. The flask was washed with nitrogen for 5 minutes. The mixture was heated to 60 ° C. and then under nitrogen for 30 minutes. After this step, the temperature was raised to 70 ° C., and potassium cyanide (8.5 g, 130 mmol, powder) was added in portions over 4 hours. At the end of the addition, the resulting mixture was stirred at 70 ° C. for 18 hours. As a result of gas chromatography (GC) analysis, at the end of this period the composition of the reaction mixture (area% by FID) was as follows: 2.45% cyanotoluene (CT), 5.91% MCT, 2-cyano -6-methoxytoluene (CMT) 90.30%.

It was also monitored using GC analysis (DB-1 column) during the run. The following table and graphs are the results from the GC data.

_

Process 2 (CCW09-50):

Dibromobis (triphenylphosphine) nickel (1.00 g, 1.34 mmol), zinc powder (0.30 g, 4.59 mmol), triphenylphosphine (50 ml three-necked flask equipped with reflux condenser, magnetic stirrer and temperature controller) 1.50 g, 5.72 mmol) and 7.5 g acetonitrile were added. The flask was washed with nitrogen for 5 minutes. The mixture was then heated to 60 ° C. and stirred for 30 minutes under nitrogen. After this step, an MCT-NMP mixture containing 10 g of MCT (63.8 mmol) and 6.3 g of NMP (63.5 mmol) was added and the mixture was stirred for an additional 15 minutes. Potassium cyanide (8.5 g, 130 mmol, powder) was then added little by little over 4 hours. At the end of the addition, the temperature was raised to 70 ° C. and the resulting mixture was stirred for a further 16 hours. As a result of GC analysis (HP-35, 15 m column), at the end of this period the composition of the mixture (area% by FID) was as follows: CT 1.28%, MCT 3.37%, CMT 92.60%, 2,6-dime Oxytoluene (DMT) 2.13%.

The reaction was also monitored using GC analysis (DB-1 column) during the run. Tables and graphs below are from GC data.

Process 3 (CCW09-52):

Dibromobis (triphenylphosphine) nickel (1.00 g, 1.34 mmol), zinc powder (0.30 g, 4.59 mmol), triphenylphosphine (50 mL three-necked flask with reflux condenser, magnetic stirrer and temperature controller) 1.50 g, 5.72 mmol) and 7.5 g acetonitrile were added. The flask was washed with nitrogen for 5 minutes. The mixture was then heated to 60 ° C. and stirred for 30 minutes under nitrogen. After this step, an MCT-NMP mixture containing 10 g of MCT (63.8 mmol) and 7.3 g of NMP (73.6 mmol) was added and the mixture was stirred for an additional 15 minutes. The temperature was then raised to 70 ° C. and potassium cyanide (8.5 g, 130 mmol, powder) was added little by little over 4 hours. At the end of the addition, the temperature was raised to 70 ° C. and the resulting mixture was stirred for a further 24 hours. As a result of GC analysis, the composition of the mixture (% area by FID) at the end of this step was as follows: CT 1.28%, MCT 3.37%, CMT 92.60%, 2,6-dimethoxytoluene (DMT) 2.13%.

The reaction was also monitored using GC analysis (DB-1 column) during the run. The following table and graphs are the results from the GC data.

Example 8 Hydrolysis of 2-cyano-6-methoxytoluene (CMT) to 3-methoxy-2-methylbenzoic acid (MMBA)

To a 3-neck 25 mL flask equipped with a thermostat, condenser and magnetic stirrer, charge 1.2 g 2-cyano-6-methoxytoluene (8.2 mmol), 2.0 g 45% aqueous potassium hydroxide solution (16.1 mmol) and 15 g ethylene glycol It was. The mixture was heated to reflux and stirred for 5 hours. The resulting mixture was cooled to ambient temperature, diluted with 30 mL of water and then extracted with methylene chloride (2 x 20 mL). The aqueous layer was acidified with 37% hydrochloric acid until pH 2 or less and then extracted with methylene chloride (2 x 30 mL). Methylene chloride extracts were mixed. After removal of methylene chloride, 1.2 g of MMBA was obtained. Yield 89%.

Example 9 Conversion of 3-methoxy-2-methylbenzoic acid to 3-hydroxy-2-methylbenzoic acid

In a 20 mL pressure tube was charged 0.50 g of 3-methoxy-2-methylbenzoic acid (3.0 mmol) and 1.52 g of 48% hydrobromic acid (9.0 mmol, 3.0 eq.). The tube was sealed and then heated to 170 ° C. in an oil bath. The mixture was stirred for 4 hours using a magnetic stirrer. Then cooled to ambient temperature. A portion of the material was removed and dried under vacuum to remove volatile components. Analysis of the residue by GC and NMR showed pure 3-hydroxy-2-methylbenzoic acid.

Example 10 Conversion of 2-cyano-6-methoxytoluene to 2-cyano-6-hydroxytoluene

Into a 20 mL pressure tube was charged 0.50 g of 2-cyano-6methoxytoluene (3.4 mmol) and 1.73 g of 48% hydrobromic acid (10.2 mmol, 3.0 eq.). The tube was sealed and then heated to 170 ° C. in an oil bath. The mixture was stirred for 4 hours using a magnetic stirrer. Then cooled to ambient temperature. A portion of the material was removed and dried under vacuum to remove volatile components. Analysis of the residue by GC and NMR showed pure 2-cyano-6-hydroxytoluene.

It is possible to change or modify the present invention without departing from the spirit and scope of the invention as defined in the claims.

As described above, according to the method of the present invention, the desired benzoic acid and benzonitrile can be produced with higher purity at lower cost.

Claims (5)

(i) reacting a compound of formula (I) with an alkali alkoxide, alkali alkoxide, alkali arylalkoxide or alkali heteroarylalkoxide in the presence of a catalyst comprising optionally copper to produce a compound of formula (IIa), and (Ii) reacting a compound of formula (IIa) with an alkali metal cyanide, acetone cyanohydrin or cuprous cyanide in the presence of a catalyst comprising nickel to form an aromatic cyano compound of formula (III) Process for the preparation of the compound.

In the above formula, Each X is independently chlorine, bromine or iodine, R is a hydrogen atom, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₂ ) alkyl, heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ the chihoen alkoxy with 1 to 3 substituents independently selected from (C ₁ -C ₆₎ alkyl, aryl, aryl (C ₁ -C ₂₎ alkyl, , Heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl, R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C ₁ -C ₂₎ alkyl or heteroaryl (C ₁ -C ₂ Alkyl, R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₅₎ alkyl or (C ₁ -C ₂₎ alkoxy (C ₁ -C ₃₎ alkyl substituted with. (i) reacting a compound of formula (I) with an alkali metal cyanide, acetone cyanohydrin or cuprous cyanide in the presence of a catalyst comprising nickel to form an aromatic cyano compound of formula (IIb); and (Ii) reacting a compound of formula (IIb) with an alkali alkoxide, alkali alkoxide, alkali aryl alkoxide or alkali heteroaryl alkoxide in the presence of a catalyst comprising optionally copper to produce a compound of formula (III) Process for the preparation of the compound of III.

In the above formula, Each X is independently chlorine, bromine or iodine, R is a hydrogen atom, (C ₁ -C ₆ ) alkyl, aryl, aryl (C ₁ -C ₂ ) alkyl, heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ the chihoen alkoxy with 1 to 3 substituents independently selected from (C ₁ -C ₆₎ alkyl, aryl, aryl (C ₁ -C ₂₎ alkyl, , Heteroaryl or heteroaryl (C ₁ -C ₂ ) alkyl, R ¹ is CHR ² R ³ , aryl, aryl (C ₁ -C ₂ ) alkyl or heteroaryl (C ₁ -C ₂ ) alkyl; Or (C ₁ -C ₃₎ alkyl and (C ₁ -C ₃₎ an independently with one to three substituents selected from alkoxy chihoen aryl, aryl (C ₁ -C ₂₎ alkyl or heteroaryl (C ₁ -C ₂ Alkyl, R ² and R ³ are each independently a hydrogen atom or (C ₁ -C ₅₎ alkyl or (C ₁ -C ₂₎ alkoxy (C ₁ -C ₃₎ alkyl substituted with. 3. The compound of claim 1, wherein each X is independently chlorine or bromine, R is a hydrogen atom or (C ₁ -C ₆ ) alkyl, and R ¹ is CHR ² R ³ , aryl or aryl (C ₁ -C ₂ ) alkyl, R ² and R ³ are each independently a hydrogen atom or a (C ₁ -C ₂ ) alkyl or substituted with methoxy And (C ₁ -C ₂ ) alkyl. 3. The catalyst of claim 1, wherein any catalyst comprising copper is copper (I), copper bromide (I), copper iodide (I), copper cyanide (I), copper (II) chloride, copper oxide (II), copper (II) sulfate and elemental copper. The catalyst of claim 1 or 2, wherein the catalyst comprising nickel is nickel (II) bromide, a mixture of zinc and triphenylphosphine, a mixture of dibromobis (triphenylphosphine) nickel, zinc and triphenylphosphine. , Dichlorobis (triphenylphosphine) nickel, a mixture of zinc and triphenylphosphine and tris (triphenylphosphine) nickel.